1. Technical Field
This disclosure relates to methods for reducing mortality in myocardial infarction patients. More specifically, this disclosure relates to the administration of an anti-inflammatory compound to myocardial infarction patients receiving a stent in connection with percutaneous transluminal coronary angioplasty.
2. Background of Related Art
Approximately 1,000,000 patients in the U.S. survive an acute myocardial infarction (MI) each year. In an acute MI, severe restriction of blood flow in the coronary conduit vessels leads to reduced oxygen delivery to the myocardium and a subsequent cascade of inflammatory reactions resulting in death (infarction) of myocardial tissue. Percutaneous transluminal coronary angioplasty (PTCA) is widely used as the primary treatment modality in many patients with coronary artery disease. PTCA can relieve myocardial ischemia in patients with coronary artery disease by reducing lumen obstruction and improving coronary flow. The use of this surgical procedure has grown rapidly, with over 500,000 PTCAs per year. Stenosis following PTCA remains a significant problem, with from 25% to 35% of the patients developing restenosis within 1 to 3 months. Restenosis results in significant morbidity and mortality and frequently necessitates further interventions such as repeat angioplasty or coronary bypass surgery.
Despite the advent of thrombolysis and percutaneous transluminal coronary angioplasty (PTCA) to restore blood flow in approximately 40-90% of treated acute MI patients, a further inflammatory reaction (termed “reperfusion injury”) results in additional tissue damage after the successful restoration of blood flow to the previously ischemic myocardium. Myocardial infarction is still associated with a high mortality/morbidity. In addition to severe long-term clinical morbidities and mortality related to post-MI pump dysfunction, short-term mortality ranges from 5% to 30%, depending in part upon successful acute revascularization, clinical presentation, co-morbidities, and site of infarction. Therefore, additional therapeutic modalities that impact myocardial tissue damage in acute MI could significantly reduce patient morbidity and mortality.
Reperfusion therapy has been shown to be beneficial in reducing mortality following acute MI. Earlier and more complete reperfusion is related to improved survival. There is, however, evidenced that reperfusion itself may result in deleterious adverse effects, including myocyte necrosis, microvascular injury, myocardial stunning, and arrhythmias. There is some debate about the clinical relevance of these phenomena. The actual mechanism of reperfusion injury has not been fully characterized but is believed to be caused by several different mechanisms: the formation of oxygen-free radicals, changes in intracellular calcium homeostasis, recruitment of neutrophils, complement activation, disturbed endothelial function, impaired cellular energetics, and alterations to the extracellular collagen matrix.
The pathogenesis of myocardial ischemic/reperfusion (MI/R) injury was investigated in a rat model of MI/R injury, during which it was noted that anti-C5 therapy significantly inhibited cell apoptosis, necrosis, and polymorphonuclear (PMN) leukocyte infiltration despite C3 deposition. This work suggests that the terminal components C5a and C5b-9 are key mediators of tissue injury in MI/R injury. The results from this experiment demonstrate the potential efficacy of anti-C5 mAb therapy in reducing both the initial tissue damage as well as the reperfusion inflammatory reaction in patients with acute MI.
Complement can be activated through either the classical or alternative pathways. These merge to a final common pathway in which C5 plays a critical role and is cleaved to form C5a and C5b. C5a is the most potent anaphylatoxin known, and has potent pro-inflammatory properties. It induces changes in smooth muscle and vascular tone, as well as increasing vascular permeability. It also activates both neutrophils and endothelial cells. C5 cleavage also leads to the formation of C5b-9 or the membrane attack complex, which causes vesiculation of platelets and endothelial cells, formation of pro-thrombotic microparticles, and activation of leukocytes and endothelial cells.
h5G1.1-scFv is an anti-C5 monoclonal antibody (mAb) that is designed to prevent the cleavage of C5 into its pro-inflammatory by-products. (See, U.S. Pat. No. 6,355,245, the disclosure of which is incorporated herein by this reference.) At the same time, blockade of the complement system at C5 preserves the patient's ability to generate C3b, which is critical for opsonization of pathogenic microorganisms and immune complex clearance.
Monoclonal antibodies directed against rat C5 were prepared and tested in vivo on rats to evaluate the role of complement in MI/R-induced apoptosis and necrosis. See, Vakeva, et al., Circulation, (22):2259-67 (1998). When administered to rats in which myocardial ischemia was induced, the anti-rat C5 mAbs reduced MI/R-induced necrosis and PMN infiltration in the rat and attenuated MI/R-induced apoptosis in the rat.
Unfortunately, most agents that have been shown to reduce infarct size in animal models of reperfusion have been disappointing when studied in large patient populations. For example, antibodies to either one or all of the four isoforms of the CD11/CD18 integrin receptor have been shown to reduce infarct size in animal studies. However in human studies, one such antibody (Hu23F2G) failed to show any effect on infarct size. (See, Faxon et al., JACC, vol. 40, pages 1199-1204, 2002.) Faxon et al. also failed to recognize any significant reduction in mortality or any relationship between mortality, antibody dosage and the use of stents during PTCA.
Thus, there is an unmet need for agents that may lessen reperfusion injury and improve mortality in the face of acute myocardial infarction. The 3 to 6 month mortality following acute MI in the 1990s is still approximately 5% to 10%, depending on the patient population studied. In addition, a substantial number of patients suffer in-hospital heart failure and subsequent re-hospitalization for congestive heart failure (CHF) in the months to years following an index MI. New adjunctive therapies to reperfusion therapy are needed to further attenuate the reperfusion injury phenomenon and improve outcomes from acute MI.
While stents have been useful in treating coronary disease, their use can cause various effects which are undesirable. For example, stents have been found to cause trauma to the walls of blood vessels resulting in medial injury that will further evolve over time. Also, stents can cause further intravascular damage and potentially distort blood flow with the creation of separate lumens within the intravascular space. Damage from stents in the vessel wall and to the flowing blood constituents can also generate debris that is carried downstream either acutely or over time. These effects, while present to some degree in different types of reperfusion therapy, are particularly prominent when reperfusion therapy is accompanied by placement of a stent.
It would be advantageous to decrease mortality in myocardial infarction patients receiving a stent in connection with percutaneous transluminal coronary angioplasty.